P697: PONATINIB IN A REAL-LIFE SETTING: A RETROSPECTIVE ANALYSIS FROM THE MONITORING REGISTRIES OF THE ITALIAN MEDICINES AGENCY (AIFA)
Authors: M. Breccia, P. P. Olimpieri, S. Celant, O. M. Olimpieri, F. Pane, A. Iurlo, V. Summa, P. Corradini, P. Russo
Journal: HemaSphere (2022)

Background: The efficacy and safety of ponatinib, a third-generation tyrosine kinase inhibitor (TKI), are mainly reported in sponsored clinical trials. Aims: The aim of this study, based on a retrospective analysis from the monitoring Registries of the Italian Medicines Agency (AIFA wMRs), is to provide real-world data on daily practice management, treatment modifications and outcome of a large cohort of chronic myeloid leukemia (CML) patients treated with ponatinib. Methods: AIFA wMRs is an administrative database whose main scope is monitoring the appropriateness of drug prescription in Italy. Information collected through the wMRS included demographic (place of birth, age, and sex) and clinical data (BCR-ABL levels, mutations and chromosomal abnormalities if evaluated), drug prescription and administration data (date of prescription and administration, dose administered, dose changes, occurrence of adverse events as yes/no dichotomic variable, reasons for treatment interruption and/or discontinuation) and response to treatment (response assessment was requested every 90 days). Subjects who had not been administered ponatinib for ≥ 120 days were adjudicated as “discontinued” even in the absence of the “end of treatment form”. Time to treatment discontinuation (TTD) was defined as the time occurring between the date of first administration and the date of treatment discontinuation for any cause, including death. Results: Overall, 666 CML subjects were eligible for analysis: 515 patients had chronic phase (CP) CML, 50 accelerated phase (AP) and 101 blast phase (BP). Median age at baseline was 58.7 years, male prevalence (57.1%). Median time from diagnosis to start of ponatinib was 2.35 years: 259 (38.9%) subjects had received 2 lines of treatment, 260 (39.0%) 3 lines and 147 (22.1%) 4 or more lines. Mutational status was available for 58.3% of patients (n=388), with a T315I mutation reported in 46 (6.9%) patients and other mutations (the most represented being E255K, F317L, Y253H and V299L) in 99 (14.9%) subjects. At baseline, 181 patients (27.2%) had arterial hypertension, 33 (5.0%) a history of arterial and/or venous thromboses, 32 (4.8%) a pre-existing ischemic heart disease, and 13 (2.0%) a history of congestive heart failure. Overall, 593 patients (89.0%) were evaluable for best response. Ten cases (1.7%, 3 AP/BP and 7 CP) did not achieve molecular response, whereas 58 patients (8.7%, 26 AP/BP patients and 32 CP) reached a BCR/ABL1 ratio between 1% and 10% IS. A MR2 (less than 1%IS) was obtained by 82 subjects (12.3%, 20 AP/BP and 62 CP patients); 128 patients (19.2%, 12 AP/BP and 116 CP patients) achieved a molecular response ranged between MR3 (0.1%) and MR4 (0.01% IS) and 266 (39.9%, 44 AP/BP and 222 CP patients) a deeper molecular response (< 0.01% IS). With a median follow-up of 14.4 months, 136 subjects (20.4%) required at least one dose reduction due to adverse events; 309 patients (46.4%) had their dose decreased in the absence of any evidence of side effects. Treatment discontinuation occurred in 144 patients (21.6%): intolerance (7.4%), primary resistance (3.5%) and acquired resistance (5.6%). Kaplan-Meier estimated TTD was 47.2 months (CI 95% 39.3 – NA) and 7.3 months (CI 95% 4.6 – 11.8) for CP and AP/BP patients, respectively. The probability of treatment discontinuation did not significantly differ for ponatinib in second, third or subsequent line of therapy (p=0.58). Summary/Conclusion: This real-life investigation shows that ponatinib dose reductions were mainly performed in the absence of reported toxicity rather than owing to the occurrence of adverse reactions.